Identification of Phenylpyrazolone Dimers as a New Class of Anti-Trypanosoma cruzi Agents

Chagas disease is becoming a worldwide problem; it is currently estimated that over six million people are infected. The two drugs in current use, benznidazole and nifurtimox, require long treatment regimens, show limited efficacy in the chronic phase of infection, and are known to cause adverse effects. Phenotypic screening of an in-house library led to the identification of 2,2′-methylenebis(5-(4-bromophenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one), a phenyldihydropyrazolone dimer, which shows an in vitro pIC₅₀ value of 5.4 against Trypanosoma cruzi. Initial optimization was done by varying substituents of the phenyl ring, after which attempts were made to replace the phenyl ring. Finally, the linker between the dimer units was varied, ultimately leading to 2,2′-methylenebis(5-(3-bromo-4-methoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (NPD-0228) as the most potent analogue. NPD-0228 has an in vitro pIC₅₀ value of 6.4 against intracellular amastigotes of T. cruzi and no apparent toxicity against the human MRC-5 cell line and murine cardiac cells.     

Top-down vs bottom-up methodologies in multi-agent system design

Traditionally, two alternative design approaches have been available to engineers: top-down and bottom-up. In the top-down approach, the design process starts with specifying the global system state and assuming that each component has global knowledge of the system, as in a centralized approach. The solution is then decentralized by replacing global knowledge with communication. In the bottom-up approach, on the other hand, the design starts with specifying requirements and capabilities of individual components, and the global behavior is said to emerge out of interactions among constituent components and between components and the environment. In this paper we present a comparative study of both approaches with particular emphasis on applications to multi-agent system engineering and robotics. We outline the generic characteristics of both approaches from the MAS perspective, and identify three elements that we believe should serve as criteria for how and when to apply either of the approaches. We demonstrate our analysis on a specific example of load balancing problem in robotics. We also show that under certain assumptions on the communication and the external environment, both bottom-up and top-down methodologies produce very similar solutions.

Molecular‐Scale Hybridization of Clay Monolayers and Conducting Polymer for Thin‐Film Supercapacitors

Development of electrode materials with well‐defined architectures is a fruitful and profitable approach for achieving highly‐efficient energy storage systems. A molecular‐scale hybrid system is presented based on the self‐assembly of CoNi‐layered double hydroxide (CoNi‐LDH) monolayers and the conducting polymer (poly(3,4‐ethylene dioxythiophene):poly(styrene sulfonate), denoted as PEDOT:PSS) into an alternating‐layer superlattice. Owing to the homogeneous interface and intimate interaction, the resulting CoNi‐LDH/PEDOT:PSS hybrid materials possess a simultaneous enhancement in ion and charge‐carrier transport and exhibit improved capacitive properties with a high specific capacitance (960 F g^–1 at 2 A g^–1) and excellent rate capability (83.7% retention at 30 A g^–1). In addition, an in‐plane supercapacitor device with an interdigital design is fabricated based on a CoNi‐LDH/PEDOT:PSS thin film, delivering a significantly enhanced energy and power output (an energy density of 46.1 Wh kg^–1 at 11.9 kW kg^–1). Its application in miniaturized devices is further demonstrated by successfully driving a photodetector. These characteristics demonstrate that the molecular‐scale assembly of LDH monolayers and the conducting polymer is promising for energy storage and conversion applications in miniaturized electronics.     

Stochastic Energy Source Access Management: Infrastructure-integrative modular plant for sustainable hydrogen-electric co-generation

The proposed Stochastic Energy Source Access Management (SESAM) comprises renewable energy sources coupled via a direct current bus with storage modules of complementary characteristics to achieve co-generation of hydrogen and electric power on a continuous duty basis. As complementary solutions, hydrogen energy storage to provide a large capacity and access-oriented storage based on magnetic, electric or kinetic energy with less capacity but a faster response time are considered. These are arranged to form a multi-level storage that can compensate stochastic fluctuations of power over diverse time scales. The developed energy management coordinates the operation of the diverse storage modules. In this context, the access-oriented storage acts as a shock absorber in order to shield fuel cells and electrolysers from fast fluctuations of wind power and load. The functions of the plant are validated through simulation using meteorological information obtained from the National Wind Technology Center in the USA. The plant is shown to provide the scheduled output of hydrogen and electric power. Since seen from its terminals SESAM behaves in the same way as a power plant with controlled fuel input, it can be readily integrated with given infrastructures.     

An efficient decision feedback equalizer for the ATSC DTV receiver

In this paper an efficient decision feedback equalizer is presented for the equalization of the received signal in the eight level vestigial sideband, Advanced Television Systems Committee, digital television system, adopting a novel detection rule for symbol detection at the output of the equalizer. The conventional hard limiter is replaced by an efficient symbol detection algorithm, based on the underlying trellis coded modulated coding of the transmitted symbols. The proposed decision device has a marginal computational cost and it can be implemented using simple combinatorial and sequential logic circuitry. When the equalizer operates in the decision directed mode, the normalized least mean squared algorithm is utilized for the adaptation of the equalizer coefficients, in a “stop-and-go” like mode, triggered by a reliability signal associated to the detected symbols. The performance of the proposed method is illustrated by typical computer simulation.     

Electron capture dissociation of tyrosine O-sulfated peptides complexed with divalent metal cations

We compare electron capture dissociation (ECD) of doubly protonated and divalent metal-adducted tyrosine O-sulfated peptides without basic amino acid residues. ECD of doubly protonated Tyr2-sulfated cholecystokinin (CCKS) and doubly protonated Tyr12-sulfated gastrin II (GST) resulted in complete loss of SO3 from all product ions. Thus, contrary to typical ECD behavior, localization of the sulfate groups was not possible. By contrast, ECD of Ca-, Mn-, Zn-, and Fe-adducted CCKS and ECD of deprotonated GST with two calcium adducts, i.e., [GST + 2Ca - H]3+, resulted in sulfated c'- and z.-type product ions with high sequence coverage, thereby allowing both sequencing and sulfate localization. In addition, divalent metal adduction provided improved positive mode ionization efficiency for these peptides. The drastically different fragmentation behavior observed in ECD of protonated and metal-adducted CCKS and GST, respectively, is proposed to be a consequence of the absence of basic amino acid residues, promoting a mobile proton-like fragmentation mechanism, including abundant sulfate loss, for protonated species. Retention of sulfate groups was also observed in electron detachment dissociation (EDD) of CCKS and GST. However, the EDD fragmentation efficiency was much lower than that of ECD and very limited fragmentation was observed in EDD of GST, precluding localization of the sulfate group in that peptide.     

A system for efficient motor learning using multimodal augmented feedback

Numerous studies have established that using various forms of augmented feedback improves human motor learning. In this paper, we present a system that enables real-time analysis of motion patterns and provides users with objective information on their performance of an executed set of motions. This information can be used to identify individual segments of improper motion early in the learning process, thus preventing improperly learned motion patterns that can be difficult to correct once fully learned. The primary purpose of the proposed system is to serve as a general tool in the research on impact of different feedback modalities on the process of motor learning, for example, in sports or rehabilitation. The key advantages of the system are high-speed and high-accuracy tracking, as well as its flexibility, as it supports various types of feedback (auditory and visual, concurrent or terminal). The practical application of the proposed system is demonstrated through the example of learning a golf swing.     

Nanoparticle Accumulation in Angiogenic Tissues: Towards Predictable Pharmacokinetics

Nanoparticles are increasingly used in medical applications such as drug delivery, imaging, and biodiagnostics, particularly for cancer. The design of nanoparticles for tumor delivery has been largely empirical, owing to a lack of quantitative data on angiogenic tissue sequestration. Using fluorescence correlation spectroscopy, the deposition rate constants of nanoparticles into angiogenic blood vessel tissue are determined. It is shown that deposition is dependent on surface charge. Moreover, the size dependency strongly suggests that nanoparticles are taken up by a passive mechanism that depends largely on geometry. These findings imply that it is possible to tune nanoparticle pharmacokinetics simply by adjusting nanoparticle size.     

Optimization of an industrial DC magnetron sputtering process for graded composition solar thermal absorbing layer

Optimization of an industrial DC magnetron sputtering process for thin graded index coatings for solar thermal absorbers is reported. The optimization concerned the main processing parameters: sputtering power, argon flow, oxygen flow, and system set-up for graded control. The purpose of the optimization was to achieve a surface with efficient solar-thermal energy conversion based on the concept graded index coating, using a metal-dielectric composite coating of nickel–nickel oxide with a continuous change in composition through the film depth profile. It was found that the optimization of the materials composition could be controlled by one parameter related to the sputtering process, the relative oxygen flow RO, defined as the ratio of applied oxygen flow to the critical oxygen flow. For optimized sputtering conditions a solar absorptance of 0.92 was obtained for a single graded index coating on aluminum for RO value of 0.8. From the materials characterization it was found that this gave a graded index coating of two thick sub-layers, a top layer of nano-sized nickel oxide grains and a base layer of nano-size metallic nickel grains with a very thin interface of a mixture of nickel and nickel oxide that was almost amorphous.